The steadily high mortality associated with melanoma is in part be due to the limitations of predicting prognosis, especially for patients with early-stge disease. While currently available clinicopathological characteristics provide some information, their ability to predict outcome in a more personalized fashion is limited. Recent studies have proposed a number of molecular predictors in pathways related to melanoma progression, but these are too general to cater the prognostic prediction to individual patients. In our study we hypothesize that germline genetic factors in the molecular pathways related to immune response or epigenetic regulation may provide biomarkers with personalized prognostic ability. We have generated preliminary experimental data in support of this hypothesis, which we eventually planned to include in our expanded R01 application, aimed at the comprehensive genetic profiling of germline and tumor specimens of patient cohorts established at the New York University Medical Center (NYUMC). With the devastating impact of Hurricane Sandy, these important preliminary experiments were lost or otherwise halted, just before the planned analysis. The goal of the current proposal is to recover this data and hence to provide pilot evidence for the common or rare variants in immune-related and epigenetic pathways and their association with clinical outcomes in melanoma. In the proposed design we plan to perform a genotyping and survival analysis using a Cox model of >400 common variants in 154 genes from immunomodulatory and epigenetic pathways including microRNA sites, in a two stage design employing 1) 642 melanoma patients, followed by a validation analysis in 2) an additional subset of 626 patients, both cohorts prospectively ascertained at NYUMC with extensive clinical information available (Specific Aim1). In Specific Aim 2, we will complement the common variant analysis with the discovery of rare mutations/variants associated with survival by targeted sequencing and an association analysis of the same 154 genes (Specific Aim 1) in two patient subsets of Ashkenazi Jewish ancestry (AJ) of extreme clinical outcomes: 50 early recurrence versus 50 late recurrence AJ patients, followed by validation on an additional 262 AJ melanoma patients. The selection of AJ ancestry will significantly improve the design by reducing the genetic heterogeneity and enhancing the analytical power by identification of founder alleles associated with survival, that are shared among AJ patients. The findings in this study will help in the recovery of our preliminary data lost or delayed by Superstorm Sandy, hence enhancing our planned large R01 proposal for comprehensive analysis of genetic alterations (germline and somatic) associated with melanoma outcomes. Most importantly, the data will provide pilot evidence of potentially novel biomarkers of melanoma prognosis with a more personalized clinical and biological potential.